The proposed Broad Institute Center for Cancer Systems Biology represents a multi-investigator effort that has several concrete goals. First, we aim to create and maintain a vibrant community of cancer biologists and computational scientists devoted to exploring the emerging field of cancer systems biology. This will involve maintaining a rich intellectual environment that rigorously develops new, and highly integrated experimental and computational approaches to cancer research. This will involve training a next generation of cancer researchers who become increasingly expert at this cancer biology/computational biology interface, through the development and dissemination of computational tools (software), cross-disciplinary training, and multimedia educational materials. In addition, the Center will take on an ambitious, multi-investigator research project aimed at identifying the essential genes (Achilles'Heels) of cancers of different types, and developing advanced computational models that use the molecular features of cancer cells to predict these essentialities. If successful, this effort would yield both new insights into the molecular circuitry of cancer cells and would also provide a new path towards personalized cancer medicine, whereby the molecular features of a patient's tumor are predictive of their response to specific therapy.